CN107428647A - 2 methoxyl groups 4 (3 (4 methoxyphenyls) the third 1 base of alkene 1) phenol and preparation method thereof - Google Patents
2 methoxyl groups 4 (3 (4 methoxyphenyls) the third 1 base of alkene 1) phenol and preparation method thereof Download PDFInfo
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- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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Abstract
The present invention relates to a kind of 2 methoxyl groups 4 (3 (4 methoxyphenyls) the third 1 base of alkene 1) phenol with new structure that can be used for prevention or treatment all diseases related to NF κ B, IKK and STAT3 and preparation method thereof.
Description
Technical field
The present invention relates to the 2- methoxyl groups -4- with new structure (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) phenol
And preparation method thereof.
Background technology
NF- κ B belong to and the related egg such as inflammatory reaction regulation, immunological regulation, Apoptosis, cell propagation, epithelial differentiation
White family, it adjusts the expression of various genes and forms the central shaft of intracellular signaling pathway.
After attempting to develop the therapeutic agent using TNF-α inhibitor, to inflammatory reaction and immune during understanding NF- κ B effect
The regulatory function of system provides new possibility for inflammatory reaction and immunization therapy, in addition, understanding Apoptosis and cell increasing
Research tumour is occurred value and metastasis is critically important.That is, it can be seen that the destiny of cell is by NF- κ B in response to which
Which gene is outside stimulus express to determine.
The inflammation that NF- κ B pass through TNF-α interleukin 1 (IL-1), interleukin-6 (IL-6), GM-CSF etc.
Property cytokine activation.This activation NF- κ B regulation chemotactic factor (CF), such as IL-8, the α of macrophage inflammatory protein (MIP) -1,
Methyl receives chemotactic protein 1 (MCP1), RANTES, eotaxin etc.；Adhesion molecule, such as E- selections
Element, vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule 1 (ELAM1), ICAM-1
(ICAM-1) etc.；Inducing enzyme, such as cyclooxygenase-2 (COX-2), induction type nitrogen oxygenase (iNOS) etc.；And cell factor
Transcription.Thus, it will be seen that NF- κ B are related to the reaction of almost all kinds of body physiological.
For example, NF- κ B not only increase inflammation, the signal transduction material of immune response, and increase and cell propagation, cell
The apoptosis important substance related to the cell cycle.Because the insufficiency of accommodation of this NF- kB activations approach causes this medium to continue
Increase, such case are similar to autoimmune disease.In addition, NF- κ B are related to cell propagation and survival by participating in regulation
Gene and the gene related to angiogenesis and transfer and also played an important role in tumorigenic phenotype is maintained.In fact,
The increase of NF- kB activities can induce the suppression to Apoptosis to reduce the therapeutic effect of cancer therapy drug, NF- κ B after anticancer therapy
Continuous expression played an important role in the generation and treatment of tumour.
In addition, NF- κ B are by adjusting encoding inducible enzyme (such as proinflammatory cytokine, adhesion molecule, chemotactic factor (CF), life
The long factor, COX-2 or iNOS) gene and also played an important role in inflammatory reaction.
It has been found that NF- κ B activity increases in epithelioma, cancerous cell line, lymthoma etc., this shows to inhibit cell
Apoptosis is to increase the growth rate of cell and transfer.In the case of the tumour that NF- κ B are activated, it is known that tumour and cancer therapy drug
React bad, because the P- glycoprotein of induction multidrug resistance is considered as the coded by said gene adjusted by NF- κ B.The opposing party
In face, fibrosarcoma or colorectal cancer cell system the suppression of NF- kB activations generate can easy inducing cell apoptosis ring
Border, cause the favourable outcome of radiotherapy or anticancer therapy.NF- kB activations pass through VEGF (VEGF), COX-2
Cause angiogenic growth with iNOS, and by matrix metalloproteinase, plasminogen activator, heparinase etc. in the invasion and attack of tumour and
Worked in transfer.
NF- κ B can be adjusted in multiple steps, therefore can complete the prevention of various diseases by suppressing NF- kB activations
And treatment.
For example, immunocyte participates in inflammation or immune response as caused by producing ROS, NO and PGE2.In such case
Under, activated as the NF- κ B of Redox-sensitive transcription factor by oxidative stress and inflammatory mediator, with inflammatory disease
In play an important role.NF- κ B activity stress be mediated by I kappa b kinases (IKKs) by oxidation and anti-inflammatory.Because NF- κ B
And/or the target of anti-inflammatory drug that IKKs is suitable as having antioxidation activity.In addition, various antioxidants (such as grape pip
Extract (gravinol), phloroglucin, pycnogenol and curcumin) made by IKK and/or NF- κ B inactivation with anti-inflammatory
With.
As example, the present inventor proposes double (the p-hydroxybenzene) -2- crotonaldehydes induction NF- κ B inactivations of 2,4-, therefore can
For use as the medicine with anti-inflammatory or Antiarthritic effect, as disclosed in Korean Patent Publication No. 2012-0094308.
In addition, the activity control on NF- κ B, it has been suggested that the purposes of various compounds.
Gravinol as the OPC extracted from grape pip suppresses the renal tubular epithelial induced by high glucose
NF- κ B nuclear transfer in cell, therefore can be used as effective anti-oxidant and antiinflammatory.Furthermore it is known that polyphenol is used as in brown alga
The phloroglucin of monomer is by suppressing NF- κ B and IKK activity and with the antioxygen for promoting antioxidant genes expression and anti-inflammatory activity
Agent activity (influence (Effect of of Kim MM, Kim the SK. phloroglucins to oxidative stress and inflammation
phloroglucinol on oxidative stress and inflammation).Food Chem Toxicol.48
(10):The 2925-33 pages (2010)).
It is also known that curcumin prevents the oxidation in retina should by making NF- κ B inactivations in diabetic
Swash and inflammation (influence of Kowluru RA, Kanwar the M. curcumins to retina oxidative stress and inflammation in diabetes
(Effects of curcumin on retinal oxidative stress and inflammation in
diabetes).Nutr Metab(Lond).16；4:8(2007)).
Meanwhile in addition to NF- κ B, signal transduction and activating transcription factor 3 (STAT3) are related to inflammation and immune response
Important transcription factor.
STAT3 is a kind of protein that inactivation is kept in cytoplasm, as the group for being referred to as " DNA binding factor "
A part is combined with DNA base sequence, and the hereditary information in DNA is transcribed into RNA transcription for adjusting.
Therefore, STAT3 participates in immune response and inflammatory reaction, to be played a crucial role in for arthritis or cancer.
For inflammatory reaction, STAT3 is played a decisive role in the synovia infiltration that IL-6 is induced in inflammatory arthritis
And in the directly expression of regulation oxidant or inflammatory mediator (such as NO, iNOS, COX-2, IL-6, IL-1 etc.) be it is important because
Son.
By making transactivated the domain ((transactivation of STAT3 by various growth factors and cell factor
Domain tyrosine residue phosphorylation in) carries out STAT3 activation.The STAT3 (p-STAT3) of this phosphorylation enters core
To induce the expression that related broad range of target gene is formed to inflammatory reaction and tumour.
Especially, STAT3 is interact and participate in NF-kB inflammation and the important transcription factor of immune response.Therefore,
The STAT3 and NF-kB p65 for being used to suppress the transcriptional activity of iNOS genes forms compound, with carry out with NF-kB physics/
Function interacts, and then stimulates cell with together with inflammatory mediator and cell factor.Once such NF-kB and STAT3 activation,
They adjust anti-apoptotic, propagation promotes and the expression of immune response gene.
Therefore, Jianzhang Wu etc. propose that chalcone derivative suppresses cell factor (such as IL-6 and tumor necrosis factor
Son) so as to which for treating various inflammatory diseases, [Jianzhang Wu etc., new synthesis chalcone derivative is as antiinflammatory
Evaluation is with finding (Evaluation and Discovery of Novel Synthetic Chalcone Derivatives
as Anti-Inflammatory Agents),J.Med,Chem.2011,54,8110-8123]。
In addition, STAT3 is related to the pathogenesis of arthritis disease, can by suppressing STAT3 activity treating and
Prevent arthritis.
Rheumatoid arthritis is chronic auto-immune disease, it is characterised in that the arthritis of synovial membrane.Therefore, class wind
Wet arthritis are the systemic autoimmune diseases as caused by chornic arthritis.Known STAT3 activity is in rheumatoid
Played an important role in arthritic pathogenic process, and various anti-inflammatory substances (such as melittin etc.) with suppress STAT3 activity
Mode suppress rheumatoid arthritis morbidity [double (the p-hydroxybenzene) -2- crotonaldehydes of Jung Ok Ban etc., (E) -2,4-
Antiarthritic, which acts through, to be suppressed STAT3 approach and is mediated (Anti-arthritis effects of (E) -2,4-bis (p-
hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway)]。
In the case where IL-21 is as the induced t cell cell factor of regulatory T-cell, B cell and NK cells, IL-21's
Increase causes STAT3 phosphorylation to reduce, so as to alleviate the symptom of autoimmune arthritis in clinical and histology.Use
The fact that, carried out research [Ryu JGs of the IL-21 for treating rheumatoid arthritis in University of Texas etc.
Deng, by suppress STAT3 signal paths mediate Th17/Treg balance and plasma B cell regulation come treat IL-21R-Fc control
Autoimmune arthritis (Treatment of IL-21R-Fc control autoimmune arthritis via processed
suppression of STAT3 signal pathwaymediated regulation of the Th17/Treg
Balance and plasma B cells), Immunol Lett.2015 2 months；163(2):143-50].
Currently, rheumatoid pass will be applied to as the tropsch imatinib of oral JAK inhibitor as antarthritic
When saving scorching patient, the expression of metalloproteinases and interferon regulation gene shows in the synovial membrane of patient with rheumatoid arthritis
Writing reduces.JAK inhibitor as proposition reduces to STAT3 phosphorylations has clinical improvementses effect [Boyle DL etc., JAK suppression
Preparation tropsch imatinib suppresses synovial membrane JAK1-STAT signal transductions (the The JAK inhibitor in rheumatoid arthritis
tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid
), arthritis Ann Rheum Dis.2014 November 14].
In addition, Jhun et al. is mentioned because red ginseng root extract significantly reduces the phosphoric acid of STAT3 in autoimmune disease
Change, to stimulate Treg cells and reduce Th17 cell quantities, so as to have therapeutic action to arthritis, [Jhun J etc., 1 red ginseng carry
Thing is taken to exempt from by adjusting the osteoclast in STAT3 paths, Th17/Treg balances and mouse and the mankind and generating to improve itself
Epidemic disease arthritis (1Red ginseng extract ameliorates autoimmune arthritis via
regulation of STAT3 pathway,Th17/Treg balance,and osteoclastogenesis in mice
and human),Mediators Inflamm.2014；2014:351856].
IL-17 be increase synovial membrane Toll-like receptor (TLR) expression to influence the cell factor of innate immune system, be class
An important factor for rheumatic arthritis is fallen ill.Check IL-17 to osteoarthritis and patient with rheumatoid arthritis into fiber finer
In born of the same parents' sample synovial cell (FLS) Toll-like receptor (TLR) expression it is influence as a result, find STAT3 block reduce by
TLR3 expression caused by IL-17 inductions, showing can be by controlling STAT3 approach to adjust the TLR3 tables in rheumatoid arthritis
Up to [Seon-Yeong Lee etc., Interleukin-17 are increased in rheumatoid arthritis fibroblast sample by STAT3 approach
Expression (the Interleukin-17increases the expression of Toll- of Toll-like receptor 3 in synovial cell
like receptor 3 via the STAT3 pathway in rheumatoid arthritis fibroblast-like
), synoviocytes Immunology, volume 141, the 3rd phase, page 353 to 361, in March, 2014].
In addition, the STAT3 signals of IL-6 mediations are required for Th17 differentiation, and in the hair of rheumatoid arthritis
Played a crucial role in disease.Check and STAT3 is suppressed to the inhibitory action of rheumatoid arthritis and to T by using JAK2 inhibitor
The adjustment effect of cell.As a result find, when applying JAK2 inhibitor, the horizontal reduction of STAT3 phosphorylations, Treg correlation molecules
Expression increase, the function of osteoclast and development are suppressed, show to control JAK2/STAT3 approach to close in treatment rheumatoid
[Park JS etc., the phase that regulatory T cells and Th17 cells are passed through by the AG490 JAK2-STAT3 blocked highly useful during section is scorching
Mutually regulation suppresses autoimmune arthritis (the JAK2-STAT3 blockade by AG490 suppresses in mouse
autoimmune arthritis in mice via reciprocal regulation ofregulatory T Cells
And Th17 cells), J Immunol.2014 May 1；192(9):4417-24].
Have in addition, the EGCG (EGCG) in green tea polyphenols is one kind in green tea
The catechin of highest bioactivity, for strengthening effective anti-oxidant and antiinflammatory action by suppressing signal and gene expression.Cause
This, Yang EJ et al. carry out various researchs, whether alleviate arthritis to investigate EGCG and prevent destruction of joint, significantly reduce
STAT3 phosphorylations, so as to significantly reduce the expression of Th17 cells and osteoclast mark, and suppress the activity of osteoclast,
And propose that EGCG can [Yang EJ etc., EGCG passes through Th17/ as the effective therapeutic agent for autoimmune arthritis
Treg controls suppress STAT3 and HIF-1 α to weaken autoimmune arthritis (EGCG attenuates autoimmune
arthritis by inhibition of STAT3 and HIF-1αwith Th17/Treg control).PLoS
18 days One.2014 2 months；9(2):e86062].
In addition, EGCG has therapeutic action to auto-inflammatory disease and obesity.That is, EGCG is by suppressing STAT3
The expression of albumen and the differentiation of Th17 cells lose weight and reduced fatty infiltration in hepatic tissue and improvement arthritis and various
[Byun JK etc., EGCG pass through the balance between changing CD4+T cell subsets to inflammation index
Come the auto-inflammatory arthritis (Epigallocatechin-3-gallate for improving obesity and being aggravated by obesity
ameliorates both obesity and autoinflammatory arthritis aggravated by obesity
By altering the balance among CD4+T-cell subsets), Immunol Lett.2014 January 1；
157(1-2):51-9]。
In addition, as the material extracted from grape pip, OPC (GSPE) is the natural flavonoid for strengthening anti-inflammatory performance
Compound.Obesity be under inflammatory conditions as caused by the secretion of inflammatory cell and pro-inflammatory molecule.Show using GSPE
Control body weight increase is write, reduces fatty infiltration of liver, improves blood circulation.GSPE anti-obesic action is due to Treg cell numbers
Caused by the increase of amount and the reduction of Th17 cell quantities.In this case, the reduction of Th17 cell quantities is main with being used as
Significantly inhibiting for the STAT3 phosphorylations of transcription factor is relevant.That is, GSPE can be used for by suppressing STAT3 activity
Treat the immunological diseases as caused by STAT3 overactivities, such as autoimmune disease and metabolic disorder [such as Jhun JY, Portugal
The STAT3 albumen regulation of grape seed procyanidin extract mediation contributes to Treg to break up and mitigate the scorching mouse mould of fat associated joint
Inflammation (Grape seed proanthocyanidin extract-mediated regulation of STAT3 in type
proteins contributes to Treg differentiation and attenuates inflammation in a
Murine model of obesity-associated arthritis), PLoS One.2013 November 5；8(11):
e78843]。
IL-23 is novel cytokine, and targeting is discharged to promote indirectly by IL-17 of the increase from CD4 (+) T cell
CD4 (+) T cell of the differentiation of osteoclast precursor.In this case, IL-17 is used to promote from osteoclast precursor cells
Form osteoclast.In addition, IL-23 enhancings NF- κ B receptor active is to contribute to osteoclast formation.In this case,
It has been found that the approach is mediated by NF- κ B and STAT3.In the future, the IL-23 of mediation STAT3 phosphorylations is contemplated to be treatment and closed
Promising target in the scorching related osteoclasia of section.
Except the relation between STAT3 and arthritis, also cancer is occurred by STAT3 and therapy mechanism has an impact.
That is, stat protein is used to equally adjust the inflammatory reaction as caused by cell factor and immunization.Especially
Ground, stat protein it is determined that whether promote in tumor environment immune response or suppress cancer in play a significant role [Yu H etc.,
Cancer inflammation and it is immune in STAT：STAT3 leading role (STATs in cancer inflammation and
immunity:A leading role for STAT3), Nat Rev Cancer.2009 November；9(11):798-809].
Because STAT3 is the molecule for adjusting the gene related to pathogenesis of cancer and development, STAT3 is pathogenesis of cancer/enter
The first step of exhibition process.In addition, STAT3 may be by inadequately sending external signal to break up healthy cell to cause cancer
The signal transduction activity factor of disease, because in addition to Wound healing and bone regeneration, STAT3 gives birth to as the effect of transcription factor protein with tumour
Into correlation.
Yu H et al. propose that STAT3 continuous activity mediation promotes the inflammatory reaction of tumour, therefore the STAT3 and one activated
Growth, survival and the invasion and attack of a little STAT5 increases tumour cells, while suppress antitumor immune function.
That is, instantaneous inflammatory signals activation epigenetic conversion, with by positive feedback loop (such as NF- κ B,
Lin28, Let-7, IL-6 etc.) by unconverted cell transformation into cancer cell.In this case, the STAT3 activated by IL-6
Transcription factor is used to directly activate microRNA (such as miR-21 and miR-181b-1) to induce NF- κ B activity to increase, described micro-
RNA suppresses phosphatase and tensin homologous (PTEN) and tumor suppressor (CYLD).That is, STAT3 is as positive and negative
The part for being fed back to road plays a role, and the positive feedback loop is by cell factor (such as miR-21, miR-181b-1, PTEN
With CYLD etc.) basis that the epigenetic that inflammation is connected with cancer is changed [Iliopoulos D etc., passed through PTEN's and CYLD
MiR-21 and miR-181b-1 STAT3 activation is a part (STAT3 that the epigenetic that inflammation is connected with cancer is changed
activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the
Epigenetic switch linking inflammation to cancer), Mol Cell.2010 Augusts 27 days；39
(4):493-506.4]。
In addition, STAT3 is including colon cancer, liver cancer, breast cancer, prostate cancer, Huppert's disease and spongioblast
By continuous activation in the extensive tumour of knurl, because tumour cell depends on STAT3 to maintain it to grow and avoid Apoptosis.
STAT3 activates to play an important role in the sugar decomposition energy derivative and blood glucose dependence of tumour cell.Because
STAT3 adjusts Akt expression, and Akt is responsible for the necessary regulatory factor of HIF-1 up-regulations.In this case, it is possible to be because
HIF-1 (the HIF- of the main transcription regulaton factor for the Gene response that STAT3 is induced in as regulation anaerobic condition
1) played an important role in expression.
In addition, the way of two kinds of hypotypes (i.e. Non-Invasive mamillary and muscle-invasive cancer) development in human bladder carcinoma
In footpath, by STAT3 induction stem cell expansion by carcinoma in situ (CIS) approach in the clinical progress of aggressive carcinoma of urinary bladder
Key effect.That is, it was reported that when STAT3 is by continuous activation, carcinogenic substance BBN induction urinary tract precursors promote CIS
Formed and develop into muscle-invasive cancer rapidly.STAT3 is causing the urinary tract base that new CIS is formed and invasive cancer develops
Played an important role in floor cells, [STAT3 activates the effect in aggressive carcinoma of urinary bladder, and the whole world from KISTIMIRIAN becomes
Gesture bulletin summary (Stat3KISTI ), 2012-07-26].
In addition, STAT3 plays an important role in the development of cutaneum carcinoma.That is, because STAT3 is in tumour inflammatory reaction
Served a dual purpose with immunization, the technology for suppressing STAT3 expression in treatment of cancer is probably treating cancer and inflammation
High potentiality method.Therefore, STAT3 inhibitor may be used as treating the topical ceram of burned skin or precancer wound so that burn
Cancer will not be developed into by hindering skin or precancer wound.
As set forth above, it is possible to find out, the suppression of STAT3 activity is probably effectively to treat a kind of replacement of above-mentioned various diseases
Scheme, because STAT3 and the development and growth and inflammatory reaction of arthritis and cancer have various associations.
[prior art literature]
[patent document]
Patent document 1：Korean Patent Publication No. 2002-0094308
[non-patent literature]
Non-patent literature 1：Jianzhang Wu etc., Evaluation and Discovery of Novel
Synthetic Chalcone Derivatives as Anti-Inflammatory Agents,J.Med,Chem.2011,
54,8110-8123
Non-patent literature 2：Jung Ok Ban etc., Anti-arthritis effects of (E) -2,4-bis (p-
hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway
STAT3 protein could lead to new ways to prevent skin cancer, in sunrise in November 4 in 2004
Version.
Non-patent literature 3：Ryu JG etc., Treatment of IL-21R-Fc control autoimmune
arthritis via suppression of STAT3 signal pathway-mediated regulation of the
Th17/Treg balance and plasma B cells, Immunol Lett.2015 2 months；163(2):143-50
Non-patent literature 4：Boyle DL etc., The JAK inhibitor to facitinib suppresses
Synovial JAK1-STAT signalling in rheumatoid arthritis, Ann Rheum Dis.2014 11
The moon 14
Non-patent literature 5：Jhun J etc., 1 Red ginseng extract ameliorates autoimmune
arthritis via regulation of STAT3 pathway,Th17/Treg balance,and
osteoclastogenesis in mice and human,Mediators Inflamm.2014；2014:351856
Non-patent literature 6：Seon-Yeong Lee etc., Interleukin-17 increases the expression
of Toll-like receptor 3 via the STAT3 pathway in rheumatoidarthritis
Fibroblast-like synoviocytes, Immunology, volume 141, the 3rd phase, page 353 to 361, in March, 2014
Non-patent literature 7：Park JS etc., JAK2-STAT3 blockade by AG490 suppresses
autoimmune arthritis in mice via reciprocal regulation ofregulatory T Cells
And Th17 cells, J Immunol.2014 May 1；192(9):4417-24
Non-patent literature 8：Yang EJ etc., EGCG attenuates autoimmune arthritis by
Inhibition of STAT3 and HIF-1 α with Th17/Treg control.PLoS One.2014 2 months 18
Day；9(2):e86062
Non-patent literature 9：Byun JK etc., Epigallocatechin-3-gallate ameliorates both
obesity and autoinflammatory arthritis aggravated byobesity by altering the
Balance among CD4+T-cell subsets, Immunol Lett.2014 January 1；157(1-2):51-9
Non-patent literature 10：Jhun JY etc., Grape seed proanthocyanidin extract-mediated
regulation of STAT3 proteins contributes to Tregdifferentiation and
attenuates inflammation in a murine model of obesity-associated arthritis,
PLoS One.2013 November 5；8(11):e78843
Non-patent literature 11：Yu H etc., STATs in cancer inflammation and immunity:a
Leading role for STAT3, Nat Rev Cancer.2009 November；9(11):798-809
Non-patent literature 12：Iliopoulos D etc., STAT3 activation of miR-21 and miR-181b-1
via PTEN and CYLD are part of the epigenetic switch linking inflammation to
Cancer, Mol Cell.2010 Augusts 27 days；39(4):493-506.4
Non-patent literature 13：STAT3 activates the effect in aggressive carcinoma of urinary bladder, becomes from the KISTI MIRIAN whole world
Gesture bulletin summary (Stat3KISTI ), 2012-07-26
The content of the invention
Technical problem
Therefore, in order to control the activity related to NF- κ B, IKK and STAT3, the present inventor is studied in every respect
To prepare new compound, and the compound for by Heck reactions being prepared for that there is new structure.
Therefore, one aspect of the present invention provides a kind of compound with new structure and preparation method thereof.
Technical scheme
In order to solve the above problems, according to an aspect of the invention, there is provided the 2- methoxies represented by following chemical formula 1
Base -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) phenol：
[chemical formula 1]
According to another aspect of the present invention, there is provided prepare the 2- methoxyl groups -4- (3- (4- methoxyphenyls) of chemical formula 1
Propyl- 1- alkene -1- bases) phenol method, the 2- methoxyl groups -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) of the chemical formula 1
Phenol as shown in following reaction equation 1 by making the compound of chemical formula 2 be reacted with the compound of chemical formula 3 to prepare：
[reaction equation 1]
In the reaction equation 1, X is halogens.
Beneficial effect
Prevention can be used for according to the compound of the present invention or treat all diseases related to NF- κ B, IKK and STAT3.
Embodiment
According to the present invention, there is provided the new compound represented by following chemical formula 1；
[chemical formula 1]
The Compound nomenclature is that phenol is (hereinafter referred to as by 2- methoxyl groups -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases)
" MMPP "), molecular formula C17H18O3, molecular weight 270.3g/cm3。
MMPP includes its optical isomer, stereoisomer, polymorph, racemic mixture, solvate, hydration
Thing, metabolin and pharmaceutically acceptable salt.Preferably, MMPP can be (E) -2- methoxyl groups -4- (3- (4- methoxyphenyls)
Propyl- 1- alkene -1- bases) phenol.
MMPP provided by the invention can be prepared using various methods.Prepared for example, MMPP can be reacted by Heck.
Heck reactions are the coupling reactions that use palladium as catalyst, i.e., by single step reaction by aromatic group or alkene
Hydrocarbyl group is connected on alkene to prepare the reaction of the compound with unsaturated group.
Specifically, as the MMPP that chemical formula 1 represents by making the compound of chemical formula 2 and chemical formula 3 as shown in reaction equation 1
Compound react and prepare：
[reaction equation 1]
In the reaction equation 1, X is halogens.
Preferably, X is F, Cl, I or Br.It is highly preferred that I's or Br is reactive best.
In reaction equation 1, the compound of chemical formula 2 can use any compound, as long as the compound of chemical formula 2 is first
Epoxide phenol derivatives and X can be met.The reactant can be prepared directly, or can be bought and using commercially available
Reactant.According to an exemplary embodiment of the present invention, the iodo- 2- metoxyphenols of 4- are used.
In addition, the compound of chemical formula 3 is 4- allyl benzene methyl ethers, it can directly prepare or can buy and using city
The compound sold.
Reaction equation 1 can be carried out in the presence of palladium catalyst and alkali, and can add part with intensified response.
Any palladium catalyst can be used, as long as palladium catalyst is used in known coupling reaction, in the present invention simultaneously
It is not particularly limited.Typically, palladium catalyst can include being selected from by three (dibenzalacetone) two palladium (Pd2(dba)3), four
(triphenylphosphine) palladium (Pd (PPh3)4), double (triphenylphosphine) palladium bichloride (Pd (PPh3)2Cl2), double (acetonitrile) palladium bichloride (II) (Pd
(CH3CN)2Cl2), acid chloride (II) (Pd (OAc)2), palladium acetylacetonate (II) (Pd (acac)2), chlorination Allylpalladium (II) two
Polymers (Pd (allyl) Cl]2), palladium carbon (Pd/C) and palladium bichloride (II) (PdCl2) it is more than one of the group that is formed.According to this
One illustrative embodiments of invention, are used Pd (OAc)2。
As reaction promoter, for example, alkali includes：Organic or inorganic salt, such as potassium chloride, KBr, KI, chlorination
Sodium, sodium bromide, sodium iodide, ammonium chloride, ammonium bromide, ammonium iodide, tetra-n-butyl ammonium bromide, tetran-butylphosphonium bromide phosphine, the second of benzyl three
Ammonium chloride or benzyl triethyl ammonium bromide；Organic or inorganic acid, such as formic acid, acetic acid, propionic acid, carbonic acid, carbon dioxide, chlorination
Hydrogen, hydrogen bromide or hydrogen iodide；And organic or inorganic alkali, such as triethylamine, tri-n-butylamine, dimethylaniline, pyridine, hydroxide
Sodium, potassium hydroxide, sodium hydride and hydrofining.According to an exemplary embodiment of the present invention, tri-n-butylamine is used.
Based on 1 mole of palladium catalyst, the dosage of this alkali is 0.1 to 1000 mole of %, preferably 1 to 200 mole of %.
In reaction equation 1, when needed, it can promote to react with further by adding part, so as in a short time
To be reacted in high yield.
For example, it is used as part using phosphorus compound, arsenic compound, antimonial, diolefin compound and dione compounds.It is excellent
Selection of land, use the phosphine or phosphite ester as phosphorus compound.
For example, phosphine includes：Alkylphosphines, such as triethyl phosphine, three n-propyl phosphines, tri isopropyl phosphine or tri-n-butyl phosphine；With
And triaryl phosphine, such as triphenylphosphine.
For example, phosphite ester includes：Alkyl phosphite, such as triethyl phosphite, the n-propyl of phosphorous acid three, phosphorous acid
Three isopropyl esters, tri-n-butylphosphite；And triaryl phosphites, such as triphenyl.
According to an exemplary embodiment of the present invention, triphenylphosphine is used.
Based on 1 mole of palladium catalyst, the dosage of this part is 0.01 to 500 mole of %, preferably 3 to 300 moles of %.
The reaction can be carried out in the absence of a solvent, but can use solvent when needed.
Solvent can be：Ether solvents, such as diethyl ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxanes, ethylene glycol diethyl ether, dimethoxy
Base ethane, double (2- methoxy ethyls) ether, diethyl carbitol or methyl phenyl ethers anisoles；Arsol, such as benzene, toluene or dimethylbenzene；
Halogenated aromatic solvents, such as chlorobenzene, dimethylformamide, dimethyl acetamide, 1-METHYLPYRROLIDONE, methylimidazole alkanone
Or acetonitrile；Or tetrahydrofuran, it can be used alone or is applied in combination with two or more mixed solvents.
In addition, reaction generally can be 1 to 200kg/cm under the inert atmosphere of nitrogen, argon gas or carbon dioxide2Reaction
Carried out under pressure.However, according to the heterocyclic secondary of formula (I) and boiling point, reaction time and the reactivity of solvent, pressure preferably exists
1 to 150kg/cm2In the range of.
Reaction temperature is usually 15 to 300 DEG C, preferably 50 to 250 DEG C.
Reaction time can change according to catalytic activity, be 0.5 to 100 hour, preferably 1 to 30 hour.On anti-
Should after the completion of technique, such as after solvent is removed by distillation, if necessary, gained compound can use such as be evaporated under reduced pressure,
Recrystallization or chromatogram purification technique and in a free form or inorganic acid salt form separation.
Prevention can be used for according to the MMPP of the present invention or treat all diseases related to NF- κ B, IKK and STAT3.
For example, MMPP can be used for prevention or treating cancer, such as lung cancer, stomach cancer, colon cancer, liver cancer, osteocarcinoma, cancer of pancreas,
Cutaneum carcinoma, head and neck cancer, skin or intraocular melanoma, liver cancer, uterine cancer, oophoroma, the carcinoma of the rectum, cancer of anus, colon cancer, mammary gland
Cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical carcinoma, Hodgkin's disease, cancer of the esophagus, carcinoma of small intestine, endocrine cancer, thyroid cancer, by first shape
Gland cancer, adrenal, soft tissue sarcoma, carcinoma of urethra, carcinoma of penis, prostate cancer, chronic or acute leukemia, lymphocyte lymph
Knurl, carcinoma of urinary bladder, kidney or carcinoma of urethra, clear-cell carcinoma, prostate cancer, cancer of pancreas, colon cancer, the cancer of the esophagus, head and neck cancer, carcinoma of renal pelvis, CNS
Tumour, primary CNS lymphoma, tumor of spinal cord, brain stem glioma, pituitary adenoma etc..
In addition, MMPP can apply to various immunological diseases, and can be for example applied to related to various immune responses
Disease, such as：Inflammatory disease, such as plasmacytosis, hyperimmune globulin mass formed by blood stasis, anaemia, ephritis, cachexia, herding
Industry disease, blood vessel hyperplasia ephritis, uveitis, chronic thyroiditis, delayed allergy, Crohn disease, pancreatitis, burning
Property essential atrophy disease, diabetes and Alzheimer's；Autoimmune disease, such as atopic dermatitis, rheumatoid close
Save inflammation, osteoarthritis, psoriasis, asthma, graft versus host disease(GVH disease), immune deficiency, systemic loupus erythematosus and multiple sclerosis
Disease；Metabolic disease, such as osteoporosis, artery sclerosis and myocardial infarction.
Especially, MMPP of the invention suppressed by targetting various above-mentioned therapeutic agents before the inflammation expression phase NF- κ B,
IKK and STAT3 activity fundamentally blocks the generation of TNF-α, and can be true for the disease relevant with diseases associated with inflammation
Various effects are protected, without any side effect as caused by directly suppressing TNF-α, the side effect has been considered as conventional therapy agent
The shortcomings that,.
Hereinafter, the structure of the present invention is described in more detail with reference to embodiment.It will be appreciated, however, that provide
Following examples disclosed herein help to understand the present invention, it is no intended to limit the scope of the present invention.
The preparation of [embodiment 1] 2- methoxyl groups -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) phenol
The iodo- 2- metoxyphenols (500mg, 2.0mmol) of 4- and 4- allyl benzenes methyl ether (313mg, 2.0mmol) are put into
In 25mL flask reactors, triphenylphosphine (105mg, 0.4mmol), Pd (OAc) are added2(44.9mg, 0.2mmol) and tri-n-butylamine
(451mg, 1.9mmol).Then, gained mixture is reacted 2 hours at 45 DEG C.
Gained compound by silica flash chromatography (hexane/ethyl acetate, 3:1, v/v) purify, to obtain to be dark brown
The title compound (119mg, yield 22%) of color liquid.
- high resolution mass spectrum (HRMS；ESI) m/z [M+H]+cacld.271.1329,271.1332 are found
-1H-NMR:d(CDCl3) 7.32 (d, 2H, J=8.0Hz), 6.88 (d, 1H, J=9.0Hz), 6.86 (d, 2H, J=
9.0Hz), 6.76 (d, 1H, J=8.0Hz), 6.75 (s, 1H), 6.40 (d, 1H, J=16.0Hz), 6.21 (dt, 1H, J=
16.0Hz, J=6.5Hz), 5.54 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.48 (d, 2H, 7.0Hz).
Industrial usability
According to the present invention 2- methoxyl groups -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) phenol can be used for prevention or
The treatment all diseases related to NF- κ B, IKK and STAT3.
Claims (5)
1. 2- methoxyl groups -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) phenol represented by following chemical formula 1：
[chemical formula 1]
A kind of 2. 2- methoxyl groups -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) phenol for being represented by chemical formula 1 of preparing
Method, described 2- methoxyl groups -4- (3- (4- methoxyphenyls) propyl- 1- alkene -1- bases) phenol represented by chemical formula 1 pass through as follows
The compound of chemical formula 2 is reacted with the compound of chemical formula 3 shown in row reaction equation 1 and prepare：
[reaction equation 1]
In the reaction equation 1, X is halogens.
3. according to the method for claim 2, wherein, the X is F, Cl, I or Br.
4. according to the method for claim 2, wherein, the reaction is carried out in the presence of palladium catalyst and alkali.
5. according to the method for claim 2, wherein, the reaction is by it is possible to additionally incorporate the part comprising phosphine or phosphite ester
Come carry out.
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| KR1020150031372A KR101609323B1 (en) | 2015-03-06 | 2015-03-06 | 2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol and a preparation method thereof |
| KR10-2015-0031372 | 2015-03-06 | ||
| PCT/KR2016/002124 WO2016144042A1 (en) | 2015-03-06 | 2016-03-03 | 2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol and preparation method therefor |
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| KR102236686B1 (en) | 2018-09-13 | 2021-04-06 | 오토텔릭바이오 주식회사 | Composition for treating or preventing cancer comprising 2-(3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2- quinazolinylsulfanyl)-N-(4-ethylphenyl)butanamide as an active ingredient |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101679228A (en) * | 2007-06-05 | 2010-03-24 | 盖尔德马研究及发展公司 | Novel derivatives of 3-phenyl acrylic acid activating PPAR-type receptors, method for preparing same and use thereof in cosmetic or pharmaceutical compositions |
| KR20120094308A (en) * | 2011-02-16 | 2012-08-24 | 충북대학교 산학협력단 | Pharmaceutical composition comprising 2,4-bis(p-hydroxyphenyl)-2-butenal for treating and preventing inflammation and arthritis disease |
| CN103261139A (en) * | 2010-12-23 | 2013-08-21 | 奇华顿股份有限公司 | Compounds capable of releasing fragrant compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679228A (en) * | 2007-06-05 | 2010-03-24 | 盖尔德马研究及发展公司 | Novel derivatives of 3-phenyl acrylic acid activating PPAR-type receptors, method for preparing same and use thereof in cosmetic or pharmaceutical compositions |
| CN103261139A (en) * | 2010-12-23 | 2013-08-21 | 奇华顿股份有限公司 | Compounds capable of releasing fragrant compounds |
| KR20120094308A (en) * | 2011-02-16 | 2012-08-24 | 충북대학교 산학협력단 | Pharmaceutical composition comprising 2,4-bis(p-hydroxyphenyl)-2-butenal for treating and preventing inflammation and arthritis disease |
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| SEBASTIAN STRYCH，等: "Biomimetic Synthesis of Santalin A,B and Santarubin A,B, the Major Colorants of Red Sandalwood", 《ANGEW. CHEM. INT. ED.》 * |
| VINAY PATHAK，等: "Syntheses of 2-methoxyestradiol and eugenol template based diarylpropenes as non-steroidal anticancer agents", 《RSC ADVANCES》 * |
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| KR101609323B1 (en) | 2016-04-05 |
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